Na+ K+ ATPase (NKA) is a determinant of the cellular membrane potential and can contribute to the vascular smooth muscle reactivity and tone and myocardial contractility, and thus may play a role in development and/or maintenance of hypertension. The enzyme is composed of alpha- and beta-subunits, and several isoforms of the enzyme exist. The isoforms are expressed in a species- and tissue-specific manner and appear to be differently regulated in both health and disease states. However, information on the functional significance of the isozymes and the regulation of these proteins is far from complete. Especially, the role of individual isoforms and the mode of their regulation in hypertension is not known. The investigators and others have previously shown that NKA catalytic alpha-2 subunit gene and protein expressions are downregulated both in the heart and in the vasculature in several animal models of hypertension. They have also shown that the downregulation in the heart can be reversed by antihypertensive treatment in genetically hypertensive rats. They wish to determine whether this downregulation of the NKA alpha-subunit in the vasculature is a compensatory reaction or a causal factor in hypertension. The proposed studies will differentiate between these possibilities by testing specific hypotheses about the mechanisms underlying the alterations in the alpha-2 subunit and the functional consequences of this regulation (ion transport and the vascular tone and reactivity) in hypertension. The specific aims are: (1) To test the veracity of the hypothesis that intravascular pressure is a signal for downregulation of the alpha-2 isoform of NKA in the vascular smooth muscle. This hypothesis predicts that there will be decreases in mRNA for the alpha-2 subunit under the following conditions: (a) in vitro, cultured aortic smooth muscle cells exposed to sustained pulsating stretch, (b) isolated perfused rat tail artery exposed to sustained elevated perfusion pressure, and (c) in the vasculature of rats with hypertension, which should be reversed with antihypertensive treatment. (2) To test the veracity of the hypothesis that pressure stimulus results in an alteration in (a) the activity of the vascular smooth muscle Na-pump, and (b) the contractile responsiveness of the vasculature. We will: (a) measure the Na-pump activity and the [3H]ouabain binding sites in cells exposed to stretch. This hypothesis predicts that both the Na-pump activity and the ouabain binding will decrease with stretching. (b) determine the vascular responsiveness to vasoactive agents and measure the Na-pump activity in tail arteries after perfusing with high pressure for a prolonged period. This hypothesis predicts a decrease in Na-pump activity and an enhancement of vascular reactivity. (3) If the data from Aims 1 and 2 fail to support the hypothesis that pressure downregulates alpha-2, the alternate hypothesis that alpha-2 downregulation is a causal factor to hypertension by contributing to increased vascular reactivity. We will obtain indirect evidence by downregulating the alpha-2 subunit and determining the vascular responsiveness. This hypothesis predicts that the responsiveness of the arteries will increase as a result of alpha-2 downregulation.